The pancreas is a long and slender organ, approximately 20 cm long, which lies behind the stomach. The pancreas has functions in producing pancreatic juice that assists digestion of food (external secretion) and in producing a hormone required for regulating blood sugar levels, such as insulin and glucagon (internal secretion).
Examples of pancreatic diseases include diabetes, pancreatitis, and pancreatic cancer.
Among them, pancreatic cancer does not show characteristic symptoms in an early stage and advances quickly, thus detection of pancreatic cancer tends to be delayed and it is often detected as advanced cancer. Pancreatic cancer is one of the most lethal human cancers, with 1-year and 5-year survival rates below 25% and 5%, respectively (Non Patent Literatures 1 to 5). Conventional treatment approaches, including surgery, radiation, chemotherapy, and their combinations have had little impact on the course of this aggressive neoplasm.
Although gemcitabine has been widely used in recent years as standard systemic chemotherapy for patients with unresectable pancreatic cancer (Non Patent Literature 6), the response rate is only approximately 10% and the median survival time is approximately 6 months (Non Patent Literature 7). Trials comparing gemcitabine plus various cytotoxic and/or molecular targeted agents with gemcitabine alone have shown no improvement in response or survival (Non Patent Literatures 2 to 4). The very poor prognosis of patients with advanced pancreatic cancer and the absence of efficient new drugs suggest the need for innovative modalities that may improve clinical response to available chemotherapies.
Regional chemotherapy techniques, including arterial infusion, chemoembolization, and perfusion, have been used to treat patients with advanced pancreatic cancer. More recently, arterial infusion chemotherapy has shown promise in patients with non-resectable pancreatic cancer (Non Patent Literatures 8 and 9). The pharmacological rationale for regional drug delivery is to increase drug concentrations at tumor sites and limit systemic drug exposure and its sequelae (Non Patent Literature 10). Since these anticancer drugs administered by arterial infusion ultimately enter the systemic circulation, the dose of the anticancer drugs must be strictly limited.
As such, there is currently no known local therapy in which a drug administered to the pancreas does not leak outside the pancreas. That is, in the present circumstances, a drug leaks outside the pancreas more or less even in a local therapy, thus causing a such dilemma that when a drug having high therapeutic effects for a lesion is used, side effects are caused by the systemic circulation, and conversely, when a drug having low therapeutic effects for a lesion is used in order to suppress side effects caused by the systemic circulation, the therapeutic effects for a lesion is reduced.
On the other hand, as a therapeutic method of congenital genetic diseases, cancers, peripheral vascular diseases, ischemic heart diseases, neurodegenerative diseases, viral infectious diseases, and the like, studies of clinical tests and the like involving a gene therapy have been recently conducted in various countries such as the United States of America.
A gene therapy is defined that a gene or a cell in which a gene is transferred is administered in a human body for the purpose of treating diseases (Japanese Guideline for Gene Therapy Clinical Research) and expected to be an effective therapeutic method not only for inherited diseases, but also for intractable diseases such as life-style related diseases and cancers.
As a gene therapy, clinical studies and the like of an oncogene therapy, in which a vector having a transgene integrated is directly injected into tumors, have been conducted.
For example, it is reported that as a result of directly injecting an adenovirus vector having HSV-tk integrated into prostate cancer and then continuously performing intravenous administration of ganciclovir for two weeks, a reduction of PSA (prostate specific antigen) as a marker of prostate cancer was observed without having a particularly severe adverse event in 6 out of 8 cases (Non Patent Literature 11). It is also reported that, in clinical tests where an adenovirus vector having the p53 gene integrated was used for targeting non-small-cell lung cancer and esophagus squamous epithelium carcinoma, both having a mutation in p53, the normal p53 was expressed in the tumors and anti-tumor effects were observed (Non Patent Literatures 12 and 13).
As seen in the clinical studies of prostate cancer in Non Patent Literature 11, a gene therapy has been producing good results to some extent for cancer in organs in which a drug is easily injected. However, for example, for organs located in the abdomen such as the pancreas, only known method of supplying a drug is a method involving systemic exposure of the drug, such as arterial infusion therapy, thus a gene therapeutic drug cannot be supplied in a concentrated manner and good results are not obtained.
Further, in a gene therapeutic method, a vector is used for increasing a transfer efficiency of a gene into a target cell. Among the vectors studied so far, the ones having a high gene transfer efficiency tend to have high side effects on normal cells. In order to realize a gene therapy for pancreatic cancer, a method, in which a vector having side effects does not leak outside the pancreas, needs to be established. However, at the present stage, there is no known local therapy in which a leakage of a drug is prevented strictly enough to allow a gene therapy.
Furthermore, a gene therapeutic drug is very expensive compared to a conventional drug such as an anticancer drug, thus it also needs to restrain an amount of the drug used in a single clinical test for reducing costs per clinical test.